Sirtulin–Ypk1 regulation axis governs the TOR signaling pathway and fungal pathogenicity in Cryptococcus neoformans

• Published in: Microbiology spectrum Vol. 12; no. 8; p. e0003824
• Main Authors: Chai, Zhenghua, Li, Yanjian, Zhang, Jing, Ding, Chen, Tong, Xiujuan, Zhang, Zhijie
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 24.06.2024
• Subjects: acetylation; Cryptococcus neoformans; deacetylase; fungal infection; fungal pathogenicity; Genetics and Molecular Biology; Research Article; acetylation; fungal pathogenicity; fungal infection; deacetylase; Cryptococcus neoformans
• ISSN: 2165-0497; 2165-0497
• DOI: 10.1128/spectrum.00038-24

Cryptococcus neoformans is an important opportunistic fungal pathogen in humans. While there are currently few effective antifungal treatments, the absence of novel molecular targets in fungal pathogenicity hinders the development of new drugs. There is increasing evidence that protein post-translational modifications (PTMs) can modulate the pathogenicity of fungi. In this study, we discovered that the pathogenicity of C. neoformans was significantly impacted by the dynamic acetylation changes of Ypk1, the immediate downstream target of the TOR complex. We discovered that Ypk1 is acetylated at lysines 315 and 502, both of which are within kinase functional domains. Deacetylation of Ypk1 is necessary for formation of the capsule structure, the response to the TOR pathway inhibitor rapamycin, nutrient utilization, and host infection. We also demonstrate that the sirtuin protein family is involved in the Ypk1 deacetylation mechanism. We anticipate that the sirtuin–Ypk1 regulation axis could be used as a potential target for the development of antifungal medications.